Protection against hemorrhagic shock in mice genetically deficient in poly(ADP-ribose)polymerase

Abstract

Hemorrhagic shock (HS) and resuscitation leads to widespread production of oxidant species. Activation of the enzyme poly(ADPribose) polymerase (PARP) has been shown to contribute to cell necrosis and organ failure in various disease conditions associated with oxidative stress. We tested the hypothesis whether PARP activation plays a role in the multiple organ dysfunction complicating HS and resuscitation in a murine model of HS and resuscitation by using mice genetically deficient in PARP (PARP ؊͞؊ ) and their wild-type littermates (PARP ؉͞؉ ). Animals were bled to a mean blood pressure of 45 mmHg (1 mmHg ‫؍‬ 133 Pa) and resuscitated after 45 min with isotonic saline (2؋ volume of shed blood). There was a massive activation of PARP, detected by poly(ADP-ribose) immunohistochemistry, which localized to the areas of the most severe intestinal injury, i.e., the necrotic epithelial cells at the tip of the intestinal villi, and colocalized with tyrosine nitration, an index of peroxynitrite generation. Intestinal PARP activation resulted in gut hyperpermeability, which developed in PARP ؉͞؉ but not PARP ؊͞؊ mice. PARP ؊͞؊ mice were also protected from the rapid decrease in blood pressure after resuscitation and showed an increased survival time, as well as reduced lung neutrophil sequestration. The beneficial effects of PARP suppression were not related to a modulation of the NO pathway nor to a modulation of signaling through IL-6, which similarly increased in both PARP ؉͞؉ and PARP ؊͞؊ mice exposed to HS. We propose that PARP activation and associated cell injury (necrosis) plays a crucial role in the intestinal injury, cardiovascular failure, and multiple organ damage associated with resuscitated HS.gut ͉ knockout H emorrhagic shock (HS) and resuscitation trigger the expression of a cascade of inflammatory mediators, resulting in tissue damage, multiple organ dysfunction, and eventually death. Regional hypoxia associated with hemorrhage and oxidative stress during resuscitation contribute to the development of this systemic inflammatory response (1). In recent years, evidence has accumulated that an important mechanism of tissue injury during oxidative stress was the activation of PARP [also termed poly(ADP-ribose) (PAR) synthetase or PARS], an enzyme abundantly present in the nucleus of eukaryotic cells (2). Activation of PARP is triggered by oxidant-mediated DNA single-strand breaks and initiates an energy-consuming futile intracellular cycle, leading to the rapid depletion of the cellular stores of NAD ϩ (the substrate of PARP) and ATP, resulting in cell dysfunction and necrotic-type cell death (3, 4). DNA single-strand breakage, PARP activation, and cell death have been demonstrated in vitro in cells exposed to various oxygencentered free radicals (2), as well as to peroxynitrite, a reactive nitrogen species formed from the rapid reaction of NO with superoxide radical (5). In vivo, PARP activation has also been convincingly shown to act as a common effector of oxidantdependant damage in various pathophysiologi...

Pyruvate improves redox status and decreases indicators of hepatic apoptosis during hemorrhagic shock in swine

“…In comparing mice genetically deficient in PARP with wild-type mice, the results indicate that PARP activation was associated with hepatic dysfunction and decreases survival. However, this damaging sequence of events was not seen in PARP-deficient mice with hemorrhagic shock (24). In addition, other studies of rats undergoing hemorrhagic shock and resuscitation have shown that the prevention of PARP activation decreases hepatic damage and dysfunction (28,45).…”

“…glutathione; redox state; caspases DESPITE ADVANCES IN THE EARLY CARE of trauma victims over the past two decades, multiple organ failure (MOF) continues to be a major factor in the morbidity and mortality that occurs after resuscitation from hemorrhagic shock (16). While there are numerous factors that influence the development of MOF, there is increasing evidence that hepatic dysfunction plays a central role (21,24,42,43). Experimental studies have shown that despite acute aggressive resuscitation, there is a consistent depression in microvascular blood flow that results in hypoperfusion and progressive hepatic dysfunction (32,42,43).…”

“…creasing evidence that hepatic dysfunction plays a central role (21,24,42,43). Experimental studies have shown that despite acute aggressive resuscitation, there is a consistent depression in microvascular blood flow that results in hypoperfusion and progressive hepatic dysfunction (32,42,43).…”

“…While necrosis results from overwhelming cellular deenergization, recent studies suggest that the final common pathway for liver dysfunction after hemorrhagic shock is apoptosis (24). The induction of apoptosis results from transient opening of the mitochondrial permeability transition pore (MPTP) with the release of cytochrome c, further generation of oxidative stress, release of intracellular Ca 2ϩ , and activation of a cascade of cysteine protease including caspase 3 (22,25,39).…”

Effect of N-acetylcysteine on pulmonary cell death in a controlled hemorrhagic shock model in rats

“…Considering that using fluid resuscitation alone in treating hemorrhagic shock would not be able to prevent MODS and mortality 11 , current research has diversified the search for solutions to prevent this complication. One aspect is combining drugs with fluid resuscitation solutions -drug therapy 4 .…”